A landmark clinical trial reported in the New England Journal of Medicine this week showed that an oral antibiotic, levofloxacin, taken for six months once-daily, substantially reduced the risk of developing drug-resistant tuberculosis (TB) in children. Levofloxacin reduced the risk of multidrug-resistant (MDR) TB disease in children by 56%, researchers from Stellenbosch 肆客足球 reported. The trial also showed that levofloxacin given over six months, was safe and well tolerated.
The TB-CHAMP trial was conducted in South Africa, with high burden of TB and MDR-TB, focusing mainly on children below 5 years of age. These young children exposed to TB have high risk of progressing to active TB disease and of developing severe forms of disease.
In the trial, 453 children who had been exposed to an adult with MDR-TB in their household were given levofloxacin. Only 5 (1.1%) developed MDR-TB compared to 12 (2.6%) in the placebo control group.
There were very few side events from the medicine. Specifically joint pain and tendonitis, traditionally a concern, were very uncommon in children receiving levofloxacin with only 1 child overall developing low grade tendonitis. Levofloxacin was generally well accepted by children and caregivers.
“There have been major advances around treating MDR-TB disease more effectively and safely in adults and in children, in recent years. However, there has been no rigorous evidence from clinical trials on how to prevent drug-resistant TB," said Professor Anneke Hesseling, the Principal Investigator of the TB-CHAMP trial at Stellenbosch 肆客足球. “We have now found a way to safely protect children when an adult in the household has infectious MDR-TB. The importance of safeguarding our children from drug-resistant disease cannot be underestimated. The benefit to children, their families and communities could be substantial."
Over 450,000 people develop MDR-TB each year. Drug-resistant TB can be devastating for patients and their families.
“MDR-TB remains challenging to treat, and children have always been the most neglected of all patients, with access to newer medicines lagging behind adults," said Professor James Seddon, Co-Principal Investigator on the trial. “In finding a new way to keep children safe when MDR-TB afflicts a family member, we help the whole family recover that much faster from the trauma that the disease inflicts, from a health perspective, and also from economic and mental health perspectives."
The TB-CHAMP trial included compelling work on cost and impact, showing not only cost-effectiveness, but cost savings to TB programmes. For every 1000 children offered this regimen, given a 2.5% risk of developing MDR-TB disease, there was a total health saving of $11.3 million (over R117 million), a total health gain of 30 healthy life years and a reduction of 15 MDR-TB cases and one death.
A similar study conducted in Viet Nam, the VQUIN trial, focusing on adults and adolescents, had similar findings and is also reported in the journal this week. In a unique collaboration, investigators from the TB CHAMP and V-QUIN trials combined the data from their trials across paediatric and adult populations to jointly inform new global guidelines on MDR-TB prevention. These joint combined trial findings are also reported this week in NEJM Evidence. Using both traditional meta-analysis and novel Bayesian methods developed at the Medical Research Council Clinical Trials Unit at 肆客足球 College London, the teams analysed the combined data from the two trials, and showed levofloxacin was similarly effective in adults and children.
“By carefully planning this work in advance, we have been able to present these important findings alongside the main results of the two trials, with even greater impact on global guidelines and policy" said Trinh Duong, TB-CHAMP trial statistician, who led for the combined analyses, from MRC Clinical Trials Unit at UCL. This efficient collaborative analysis strategy highlights the advantages of proactive data sharing and innovative methods to pool data, ensuring that evidence obtained from adults and children could simultaneously impact on global guidelines and access in the field to all of those at risk of developing MDR-TB.
Based on a review of this trial evidence, the World Health Organisation recommended levofloxacin for MDR-TB preventive treatment in children, adolescents and adults, in September 2024.
“Research to prevent and treat tuberculosis in children has been treated as an afterthought for far too long," said Dr Philippe Duneton, Executive Director of Unitaid, the largest multilateral funder of TB research and development globally. “Unitaid is pleased to be a part of efforts to address children's needs. This first of its kind evidence into the prevention of drug-resistant TB in children is a major advance that has the potential to protect millions of children."
TB remains one of the top causes of death in children globally and is a one of the top killers of children below 5 years of age. Fewer than 20% of children with MDR-TB are currently diagnosed and treated, making them one of the most neglected populations affected by TB. Many of these children with MDR-TB have been in close contact with someone with infectious MDR-TB. Identifying these children and the rest of their households, screening them for TB and offering them preventive treatment will be critical to find more cases and to prevent MDR-TB.
The TB-CHAMP trial was funded by Unitaid, under the BENEFIT Kids project at Stellenbosch 肆客足球. Unitaid accelerates access to innovative health products and lays the foundations for their scale-up by countries and partners. The trial was also funded by the South African Medical Research Council and the UKRI Medical Research Council through a grant to Stellenbosch 肆客足球, with support from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Global Challenges Research Fund, the Medical Research Council and Wellcome, as part of the EDCTP2 programme supported by the European Union.
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